RESEARCH ARTICLE Genetic Mutations in Early-Onset Parkinson’s Disease Mexican Patients: Molecular Testing Implications Nancy Monroy-Jaramillo, 1,2 Jorge Luis Guerrero-Camacho, 1 Mayela Rodrı ´guez-Violante, 3 Marie-Catherine Boll-Woehrlen, 4 Petra Yescas-Go ´mez, 1 Marı ´a Elisa Alonso-Vilatela, 1 and Marisol Lo ´pez-Lo ´pez 5 * 1 Neurogenetics Department, National Institute of Neurology and Neurosurgery “Manuel Velasco Sua ´rez”, Mexico City, Mexico 2 PhD Candidate in Biological and Health Sciences, Universidad Auto ´noma Metropolitana, Mexico City, Mexico 3 Movement Disorders Clinic, National Institute of Neurology and Neurosurgery “Manuel Velasco Sua ´rez”, Mexico City, Mexico 4 Neurology Division, National Institute of Neurology and Neurosurgery “Manuel Velasco Sua ´rez”, Mexico City, Mexico 5 Biological Systems Department, Universidad Auto ´noma Metropolitana, Campus Xochimilco, Mexico City, Mexico Manuscript Received: 16 July 2013; Manuscript Accepted: 29 January 2014 Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson’s disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belong- ing to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2- LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 dupli- cation for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 ob- served in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson’s disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early- onset Parkinson’s disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed. Ó 2014 Wiley Periodicals, Inc. Key words: PARK2; PINK1; DJ-1; early-onset Parkinson’s disease; digenic inheritance INTRODUCTION Recessive mutations in PARK2, PINK1, and DJ-1 genes cause early- onset Parkinson’s disease (EOPD) [Kitada et al., 1998; Bonifati et al., 2003; Valente et al., 2004]. PARK2 encodes an ubiquitin E3 ligase that tags specific substrates for protein degradation through the ubiquitin-proteasome system [Shimura et al., 2009]. Phospha- tase and tensin homolog (PTEN)-induced kinase 1 (PINK1) gene encodes a kinase that protects neurons against cell death, and regulates mitochondrial functions [Valente et al., 2004; Narendra and Youle, 2011]. DJ-1 is implicated in mitochondrial and oxida- tive-stress-related survival pathways [Lev et al., 2006]. Several interactions have been described for the proteins encoded by these How to Cite this Article: Monroy-Jaramillo N, Guerrero-Camacho JL, Rodrı´guez-Violante M, Boll-Woehrlen MC, Yescas-Go´ mez P, Alonso-Vilatela ME, Lo´ pez-Lo´ pez M. 2014. Genetic mutations in early-onset Parkinson’s disease Mexican patients: Molecular testing implications. Am J Med Genet Part B 165B:235–244. All authors declare themselves to have no conflict of interest. Grant sponsor: Consejo Nacional de Ciencia y Tecnologı´a de Me´xico; Grant number: CONACYT #140190.  Correspondence to: Marisol Lo´pez Lo´ pez, Ph.D., Biological Systems Department, Universidad Auto´ noma Metropolitana, Campus Xochimil- co, Calzada del Hueso 1100, Col. Villa Quietud, Coyoaca´n, Mexico City 04960, Mexico. E-mail: mlopez@correo.xoc.uam.mx Article first published online in Wiley Online Library (wileyonlinelibrary.com): 23 February 2014 DOI 10.1002/ajmg.b.32228 Ó 2014 Wiley Periodicals, Inc. 235 Neuropsychiatric Genetics